Protease inhibitor (Pi) phenotypes have been determined using isoelectric focusing on polyacrylamide gel in populations of normal subjects and patients with rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome and hepatocellular carcinoma. Of 80 unselected southern African Black patients with hepatocellular carcinoma, the incidence of aberrant (non-MM) phenotypes was 8.7%. In 103 age-, sex- and tribally-matched control subjects the corresponding incidence was 12.6%. None of the patients or controls had the PiZZ phenotype. 5% of patients and 1.9% of controls were heterozygous carriers of the Z gene. No patient with hepatocellular carcinoma had a subnormal serum concentration of alpha-1-antitrypsin, as assessed by rocket immuno-electrophoresis. The four patients with the heterozygous Z phenotype did not have fibrolamellar carcinomas. These findings suggest that alpha-1-antitrypsin deficiency does not play an etiologic role in hepatocellular carcinoma in southern African Blacks.